The efficacy of estrogen treatment in several injury models has been previously reported. Our own recent work has demonstrated a reduction in contusion volumes following traumatic brain injury (TBI) in female rats versus males or ovariectomized females. Although several mechanistic pathways for this neuroprotection have been explored, one that has not and is important after TBI is inflammation. TBI produces a robust inflammatory response that is both acute and chronic in duration. Several investigators using other models have reported the ability of estrogen to inhibit specific components of the inflammatory cascade. The proposed studies will assess differences between males and females after TBI with regard to post-traumatic inflammation. Four specific aims are proposed to address this issue. In specific aim 1, we will measure levels of proinflammatory cytokines and determine the cellular source of these initiators of inflammation. These studies will provide novel data on differences between males and females and in addition, by using ovariectomized females, the influence of reproductive steroids. In the second aim, we will study regional patterns of iNOS expression and determine if this response is sex and hormone-dependent. Because iNOS has been implicated in the pathogenesis of TBI, this inflammatory response to trauma requires investigation in the present setting. Specific aim 3 will assess whether estrogen's effect on the inflammatory cascade after TBI is due to antioxidant properties or receptor-mediated mechanisms. Because estrogen has been reported to effect various components of the inflammatory cascade, its effect on trauma-induced inflammatory processes requires further investigation. Results from this study will provide novel data for the potential use of neurohormones in the treatment of TBI. In the final aim, estrogen isomers or specific estrogen receptor antagonist/agonist will be administered after TBI to assess recovery of function. Taken together, these experiments will provide new data on the importance of neurohormones on structural and functional outcome after TBI. Established methods including rodent models of TBI, behavioral tests, as well as immunocytochemical and molecular approaches will be used in this proposal.